Glial cell line-derived neurotrophic factor protects against ischemia/hypoxia-induced brain injury in neonatal rat

Abstract

Ischemic/hypoxic brain damage induced in 7-day-old rats was significantly attenuated in a dose-dependent manner by intracerebral injection of glial cell line-derived neurotrophic factor (GDNF; 2 or 4 microg) within 30 min after the insult. Whereas the great majority of the vehicle-treated animals showed massive infarction involving more than 75% of the affected cerebral hemisphere, GDNF injection resulted in a remarkable reduction in both the incidence and severity of the brain damage (incidence ranging from 76% to 93% in controls to 34% to 64% in the 2.0-microg group and 7% to 29% in 4.0-microg group). The induction of immunoreactive 70-kDa heat shock protein (HSP70) in cerebral cortical neurons was also significantly reduced in GDNF-treated animals as compared to controls. The mechanisms responsible for the neuroprotective effects of GDNF remain unknown, although it has been speculated that these may be endogeneous. The higher expression of GDNF and its mRNA in developing brains may be one of the factors responsible for the relative resistance to ischemia of fetal and neonatal as opposed to adult brains. GDNF may possibly act by protecting against oxidative stress or by scavenging free radicals generated during ischemia. The results of our study strongly suggest that GDNF may prove to be an effective and potent protective agent against perinatal ischemic/hypoxic encephalopathy.

Intravenous TAT-GDNF Is Protective After Focal Cerebral Ischemia in Mice

“…29 Upregulation of GDNF mRNA in the rodent brain has been shown to occur after excitotoxicity induced by glutamate, 30 kainate, 31 or ischemia. 5 GDNF has been shown to protect neurons against oxidative stress in cultured mesencephalic neurons and glial cells, 32 against ischemia-or hypoxia-induced brain injury in neonatal rats, 33 after brain injury following permanent or transient focal cerebral ischemia in rats or mice, 9,34 after cortical cold injury, 10 and in primate models of Parkinson's disease. 35 GDNF promotes cell survival in multiple ways; recent publications showed that GDNF upregulates antiapoptotic Bcl-2 and Bcl-X L levels in apoptosis-induced rat mesencephalic neurons, resulting in a reduction in caspase activation.…”

GDNF Protects against Aluminum-Induced Apoptosis in Rabbits by Upregulating Bcl-2 and Bcl-XL and Inhibiting Mitochondrial Bax Translocation

“…Upregulation of GDNF mRNA in rat brains has been shown to occur following excitotoxicity induced by glutamate (Ho et al, 1995) or kainate (Humpel et al, 1994). GDNF has been shown to protect neurons against oxidative stress in cultured mesencephalic neurons and glial cells (Iwata-Ichikawa et al, 1999), against ischemic/hypoxic-induced brain injury in neonatal rats (Ikeda et al, 2000), after brain injury following permanent middle cerebral artery occlusion in rats (Kitagawa et al, 1998), and in primate models of Parkinson's disease (Kordower et al, 2000). The mechanisms by which GDNF exerts its neuroprotective effect are diverse, and recent evidence demonstrates that the rescue and repair of injured neurons is a consequence of an antiapoptotic action of GDNF.…”

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

“…HO-1 is also induced by fibroblast growth factor-1 in spinal cord astrocytes [23]. In a model of ischemia/hypoxia-induced brain injury, GDNF was shown to significantly reduce HSP70 induction [24,25]. After spinal cord injury, up-regulation of HSP72 was considerably reduced in brain-derived neurotrophic factor-(BDNF) or insulin like growth factor-1-pretreated rats [26].…”